In response to PQ18 we propose to address cancer-related targets that are 'undruggable' by conventional means through an innovative conjoint use of oligonucleotides and small organic molecules. There is currently tremendous interest in the therapeutic potential of antisense and siRNA oligonucleotides in cancer and other diseases, with multiple clinical trials underway. However, the inability to effectively deliver these highly polar molecules to their intracellular sites of action within tissues remains a major impediment to progress. In this PQ application we describe a novel chemical biology strategy for oligonucleotide delivery, one that is radically different from the approaches now in common use. Recent studies from our laboratory and others have shown that the pathway of cellular uptake and intracellular trafficking followed by an oligonucleotide can have a major impact on its pharmacological actions. Here we propose to manipulate oligonucleotide trafficking pathways and subsequent pharmacological effects using small organic molecules that we term OTECs ('oligonucleotide trafficking enhancer compounds'). We have already established a proof of principle for this approach using a set of small molecules that affect early endosome to trans-Golgi traffic. These agents provide a marked enhancement of oligonucleotide action in cell culture studies when used at micromolar concentrations. In the context of PQ18 we now propose to: (i) use OTECs and oligonucleotides to manipulate the functions of a transcription factor important in cancer; (ii) test whether OTEC compounds can act in xenograft tumors; (iii) use high throughput screening (HTS) to seek new, more potent OTEC-type compounds that work in the nanomolar range to enhance oligonucleotide action. Successful completion of these aims would have a transformative effect on the prospects for using oligonucleotides in cancer therapy, including the ability to address 'undruggable' targets. PUBLIC HEALTH RELEVANCE: Antisense, siRNA or splice switching oligonucleotides could provide potent tools for manipulating therapeutic targets that are 'undruggable' by conventional means. However, the pharmacological effects of oligonucleotides are often blunted because of their poor delivery into the cytosol and nucleus of tissue cells. Here we pursue a novel approach for enhancing oligonucleotide delivery by using small organic molecules that modify the intracellular trafficking of the oligonucleotides and thus enhance their pharmacological actions. I successful this approach would have a major impact on the therapeutic utility of oligonucleotides in cancer.